Hipotiroidismo congénito transitorio por defectos bialélicos del gen DUOX2. Dos casos clínicos

Abstract

Presentación de casos clínicos RESUMENEl hipotiroidismo congénito afecta a 1:2000-3000 recién nacidos detectados por pesquisa neonatal. Las oxidasas duales, DUOX1 y 2, generan agua oxigenada, lo que constituye un paso crítico en la síntesis hormonal. Se han comunicado mutaciones en el gen DUOX2 en casos de hipotiroidismo congénito transitorio y permanente. Se describen dos hermanos con hipotiroidismo congénito detectados por pesquisa neonatal, con glándula tiroides eutópica y tiroglobulina elevada. Recibieron levotiroxina hasta su reevaluación en la infancia con suspensión del tratamiento. Su función tiroidea fue normal y se consideró el cuadro como transitorio por un posible defecto de organificación. Ambos pacientes eran heterocigotos compuestos para una mutación en el exón 9 del alelo paterno (c.1057_1058delTT, p.F353PfsX36 o p.F353fsX388) y otra en el exón 11 del alelo materno (c.1271T>G, p.Y425X) del gen DUOX2. Nuestro hallazgo confirma que la magnitud del defecto de DUOX2 no se relaciona con el número de alelos afectados, lo que sugiere mecanismos compensadores en la generación de peróxido. Palabras clave: hipotiroidismo congénito, oxidasa dual, mutación, dishormonogénesis tiroidea. ABSTRACTCongenital hypothyroidism affects 1:2000-3000 newborns detected by neonatal screening programs. Dual oxidases, DUOX1 and 2, generate hydrogen peroxide needed for the thyroid hormone synthesis. Hipotiroidismo congénito transitorio por defectos bialélicos del gen DUOX2. Dos casos clínicos Transient congenital hypothyroidism due to biallelic defects of DUOX2 gene. Two clinical casesMutations in the DUOX2 gene have been described in transient and permanent congenital hypothyroidism. Two brothers with congenital hypothyroidism detected by neonatal screening with eutopic gland and elevated thyroglobulin are described. They were treated with levothyroxine until it could be suspended in both during childhood, assuming the picture as transient. Organification disorder was confirmed. Both patients were compounds heterozygous for a mutation in exon 9 of the paternal allele (c.1057_1058delTT, p.F353PfsX36 or p.F353fsX388) and in exon 11 of the maternal allele (c.1271T > G, p.Y425X) of DUOX2 gene. Our finding confirms that the magnitude of the defect of DUOX2 is not related to the number of inactivated alleles, suggesting compensatory mechanisms in the peroxide supply.

Increased risk for inflammatory bowel disease in congenital hypothyroidism supports the existence of a shared susceptibility factor

“…Children with CH that regain normal thyroid function during early life are classified as transient CH. Whereas permanent CH is caused by a variety of genetic defects in addition to DUOX2 (e.g., TPO , TG , PAX8 ) as well as sporadic developmental abnormalities (e.g., ectopic thyroid gland), partial defects in the DUOX2 enzyme complex ( DUOX2 , DUOXA2 ) are the major known genetic risk factor for transient CH 1 , 2 , 16 – 18 . Compared to a cohort of patients with permanent CH, one limited to transient CH cases is likely enriched for DUOX2 defects.…”

Clinical genetics of defects in thyroid hormone synthesis

“…It was initially claimed that biallelic inactivating mutations cause severe and permanent CH, while monoallelic mutations are associated with mild and transient hypothyroidism [36]. However, later studies have reported biallelic mutations in DUOX2 in patients with transient hypothyroidism [37,38] and have shown that monoallelic mutations can cause permanent CH [7,39]. In a sequence analysis of DUOX2, TPO, TSHR , and TG in 43 patients with CH with eutopic thyroid gland in Korea, 23 patients (53.5%) had a sequence variant in DUOX2 , indicating that DUOX2 mutations are a frequent genetic cause of thyroid dyshormonogenesis in Koreans [40].…”